Poly(ADP-ribose) polymerase inhibition improves endothelin-1-induced endothelial dysfunction in rat thoracic aorta

Abstract

Aim The aim of this study was to investigate whether poly(ADP-ribose) polymerase (PARP) inhibition improves endothelin-1 (ET-1)-induced endothelial dysfunction (ED).Methods Isolated rat thoracic aorta rings were incubated with ET-1 (10 nmol/L) in the presence or absence of either polyethylene glycol–superoxide dismutase (PEG-SOD; a cell-permeable superoxide radical scavenger, 41 U/mL) plus apocynin (a NADPH oxidase inhibitor, 300 µmol/L) or PJ34 (an inhibitor of polyADP-ribose polymerase, 3 µmol/L) for 18 h. Isometric tension studies were performed in response to acetylcholine (ACh; an endothelium-dependent vasodilator), sodium nitroprusside (SNP; an endothelium-independent vasodilator), and phenylephrine (Phe). PARP-1 and PAR (an end-product of PARP activity) expressions were evaluated by both Western blot and immunohistochemistry.Results Incubation of thoracic aorta rings with ET-1 resulted in a significant inhibition of the response to ACh, while SNP-induced relaxation was unaffected. The contractile response to Phe increased in arteries that were incubated with ET-1. PARP-1 and PAR expressions increased after ET-1 incubation. The diminished vasoreactivity as well as changes in expressions of PARP-1 and PAR in ET-1-incubated vessels were improved by both PEG-SOD plus apocynin and PJ34.Conclusion Our studies demonstrate that ED induced by ET-1 seems to be effected via oxidative stress in the thoracic aorta endothelium with subsequent activation of the PARP pathway.

Cerebral Vasodilator Property of Poly(ADP-Ribose) Polymerase Inhibitor (PJ34) in the Neonatal and Adult Mouse Is Mediated by the Nitric Oxide Pathway

“…PARP has been implicated in endothelial dysfunction in various diseases such as atherosclerosis, hypertension, diabetes, chronic heart failure, and aging [ 31 ]. In adult Wistar rats, PARP enzyme is activated in the endothelium after endothelin-1 (ET-1) incubation, and PJ34 counteracts ET-1-induced endothelial dysfunction [ 11 ]. Furthermore, PARP activation contributes to impaired eNOS-mediated vasodilation of aortas from diabetic animals [ 32 ], and to nNOS dysfunction in the maximum relaxation of in vitro gastric fundus in diabetic rats [ 33 ].…”

“…Endothelial function is rapidly recovered by pharmacological inhibition of PARP. In addition, the endothelial dysfunction either associated with hypertension and aging [ 10 ] or induced by endothelin-1 (ET-1) [ 11 ] can be prevented by pharmacological inhibition of PARP with PJ34. Furthermore, the diminished vasoreactivity in ET-1-incubated vessels is improved by PJ34 [ 11 ].…”

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Reduces Brain Damage after Stroke in the Neonatal Mouse Brain

“…In the peripheral vascular system, the endothelial dysfunction consecutive to diabetes mellitus has been related to an endothelial depletion of NADPH, an essential cofactor of the endothelial nitric oxide (NO) synthase (eNOS) [4]. Pharmacological inhibition of PARP with PJ34 (10 mg/kg) can prevent endothelial dysfunction associated with hypertension and aging [5] or induced by endothelin-1 [6]. In the cerebral vascular system, we recently reported that a single dose of the PARP inhibitor PJ34 (10 mg/kg) is able to increase cerebral blood-flow (CBF) by recruitment of the microvascular vasodilation reserve (without sex effect), and is likely to act on the endothelial function throughout life (with a major effect in the neonatal and adult brain) in the naive mouse [7].…”